ClinVar Genomic variation as it relates to human health
NM_000212.3(ITGB3):c.176T>C (p.Leu59Pro)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000212.3(ITGB3):c.176T>C (p.Leu59Pro)
Variation ID: 13558 Accession: VCV000013558.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.32 17: 47283364 (GRCh38) [ NCBI UCSC ] 17: 45360730 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 2, 2016 Feb 14, 2024 Jun 18, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000212.3:c.176T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000203.2:p.Leu59Pro missense NM_000212.2(ITGB3):c.176T>C NC_000017.11:g.47283364T>C NC_000017.10:g.45360730T>C NG_008332.2:g.34523T>C LRG_481:g.34523T>C LRG_481t1:c.176T>C LRG_481p1:p.Leu59Pro P05106:p.Leu59Pro - Protein change
- L59P
- Other names
- L33P
- Canonical SPDI
- NC_000017.11:47283363:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.08886 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.08886
1000 Genomes Project 30x 0.08994
The Genome Aggregation Database (gnomAD), exomes 0.12106
Exome Aggregation Consortium (ExAC) 0.12354
Trans-Omics for Precision Medicine (TOPMed) 0.12359
The Genome Aggregation Database (gnomAD) 0.13037
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ITGB3 | No evidence available | No evidence available |
GRCh38 GRCh37 |
600 | 784 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Benign (1) |
no assertion criteria provided
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Jan 1, 2007 | RCV000014519.16 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
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May 31, 2017 | RCV000246922.18 | |
Benign (2) |
reviewed by expert panel
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Jun 18, 2020 | RCV000383813.14 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV001517663.16 | |
risk factor (1) |
no assertion criteria provided
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Jan 1, 2007 | RCV001799606.11 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Benign
(Jun 18, 2020)
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reviewed by expert panel
Method: curation
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Glanzmann thrombasthenia
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen
Accession: SCV001397584.2
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
The ITGB3 c.176T>C (p.Leu59Pro) missense variant has been reported many times in the literature as an alloantigenic site. This variant has been observed in cis … (more)
The ITGB3 c.176T>C (p.Leu59Pro) missense variant has been reported many times in the literature as an alloantigenic site. This variant has been observed in cis with several other Glanzmann thrombasthenia variants, including the pathogenic c.224del frameshift variant (PMID: 25728920). It is present in gnomAD at an overall allele frequency of 0.1223 (and 0.1550 in the non-Finnish European population). Computational evidence suggest no impact on the gene/gene product, with a REVEL score of 0.217. Functional studies in CHO cells have shown no deleterious effect on surface expression or fibrinogen binding (PMID: 10727448). In summary, this variant meets criteria to be classified as benign for GT. GT-specific criteria applied: BA1, BS3, BP2, BP4. (less)
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Benign
(May 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Specified
Affected status: unknown
Allele origin:
germline
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Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV000864331.1
First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019 |
Comment:
BA1, BP4, BP6; This alteration has an allele frequency that is greater than 5% healthy populations (ExAC/gnomAD), is predicted to be tolerated by multiple functional … (more)
BA1, BP4, BP6; This alteration has an allele frequency that is greater than 5% healthy populations (ExAC/gnomAD), is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). (less)
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Benign
(Mar 06, 2018)
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criteria provided, single submitter
Method: clinical testing
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Glanzmann thrombasthenia 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000403732.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001726205.4
First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024 |
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Benign
(-)
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criteria provided, single submitter
Method: clinical testing
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NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000302998.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Benign
(Jun 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001757991.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 29462793, 29965811, 29038237, 29117201, 11723016, 2565345, 18657307, 22133274, 23155369, 20472470, 10727448, 15826939, 11028489, 24720773, 21919778, 21109038, … (more)
This variant is associated with the following publications: (PMID: 29462793, 29965811, 29038237, 29117201, 11723016, 2565345, 18657307, 22133274, 23155369, 20472470, 10727448, 15826939, 11028489, 24720773, 21919778, 21109038, 21813062, 19245802, 19388931, 18214290, 15609125, 19530321, 10195947, 21353223, 18836720, 21241403) (less)
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Benign
(Jan 01, 2007)
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no assertion criteria provided
Method: literature only
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PL(A1)/(A2) ALLOANTIGEN POLYMORPHISM
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034770.7
First in ClinVar: Apr 04, 2013 Last updated: Jul 09, 2022 |
Comment on evidence:
The molecular basis of the platelet-specific alloantigen system Pl(A) is a 1565T-C transition in exon 2 of the ITGB3 gene, resulting in a leu33-to-pro (L33P) … (more)
The molecular basis of the platelet-specific alloantigen system Pl(A) is a 1565T-C transition in exon 2 of the ITGB3 gene, resulting in a leu33-to-pro (L33P) substitution which corresponds to Pl(A1) and Pl(A2), respectively (Newman et al., 1989). Pl(A) is also known as alloantigen Zw. Kim et al. (1995) determined the allelic frequencies of Pl(A1) and Pl(A2) in African Americans, whites, and Koreans living in the metropolitan Baltimore area. Myocardial Infarction, Susceptibility to Using a monoclonal antibody that specifically distinguished Pl(A1) from Pl(A2), Weiss et al. (1995) observed an unexpected high frequency of family members homozygous for the A2 allele in kindreds with a high prevalence of acute coronary events at a relatively young age (under 60 years). In a case-control study, Weiss et al. (1996) found that the A2 allele was 2.1 times more prevalent among 71 patients with myocardial infarction (see 608446) or unstable angina than among controls (39.4% vs 19.1%, respectively; P = 0.01). In a subgroup of patients whose disease began before the age of 60 years, the prevalence of the A2 allele was 50%, a value that was 3.6 times that among control subjects under 60 years of age (13.9%; P = 0.002), yielding an odds ratio (OR) of 2.8 for those with the A2 allele. In patients less than 60 years of age at the onset of disease, the OR was 6.2. Goldschmidt-Clermont et al. (1996) reported without supporting data that the other major polymorphisms were not associated with myocardial infarction: Ko(a), Ko(b), Bak(a), Bak(b), Pen(a), Pen(b), Br(a), and Br(b). Goldschmidt-Clermont et al. (1996) presented evidence that Sergei Grinkov, twice Olympic pairs figure skating gold medalist, was heterozygous for the A1/A2 polymorphism and suggested that this may have been related to his precocious coronary artery disease. Grinkov, aged 28, collapsed suddenly while training on the ice rink in Lake Placid, New York, and could not be resuscitated. Necropsy showed severe coronary artery disease and a recent (4- to 6-hour-old) anteroseptal myocardial infarction (MI). He had never sought medical attention for a heart problem. He was not a smoker, did not use drugs or medications, did not have hypertension or diabetes mellitus, his total cholesterol and lipid profiles were unremarkable, and he trained for several hours daily. Significantly, his father died suddenly at the age of 52 years. See the lay account by Grinkov's widow, Ekaterina Gordeeva (1996). Goldschmidt-Clermont et al. (1999) genotyped 116 asymptomatic sibs (60 Caucasians, 56 Afro-Caribbeans) of patients with coronary heart disease manifested before the age of 60 years for the Pl(A) polymorphism. A control cohort consisted of 268 individuals (168 Caucasians, 100 Afro-Caribbeans) who were matched for race and geographic area but were free of coronary heart disease. The authors also characterized the sib cohort for other atherogenic and thrombogenic risk factors. The results supported the hypothesis that the prevalence of Pl(A2)-positive individuals is high in kindreds with premature coronary heart disease. Hence, like the established risk factors that tend to cluster in families with premature coronary heart disease and contribute strongly to the accelerated atherosclerotic process affecting these individuals, the Pl(A2) polymorphism of GP IIIa may represent an inherited risk that promotes the thromboembolic complications of coronary heart disease. That these asymptomatic sibs had overall less-established risk factors than their Pl(A1) counterparts may provide an explanation for why they remained asymptomatic despite their Pl(A2) positivity. In a cross-sectional study of patients with a history of myocardial infarction and in matched controls from the Finnish population, Pastinen et al. (1998) analyzed common variants of 8 genes implicated previously as risk factors for coronary heart disease or MI. The most common low density lipoprotein receptor (LDLR; 606945) mutations in Finland were also included in the analysis. Multiplex genotyping of the target genes was performed using a specific and efficient array-based minisequencing system. The 4G allele of the PAI1 (173360) gene (P less than 0.05) and the Pl(A2) allele of the glycoprotein IIIa gene (P less than 0.01) were associated with an increased risk of MI in the Finnish study population. They found that the combined effect of these risk alleles conferred a high risk for the development of MI (OR = 4.5, P = 0.001), which was particularly prominent in male subjects (OR = 6.4, P = 0.0005). The observation of 2 separate genes contributing an additive risk of developing MI exemplified the advantages of multiplex analysis of genetic variation. Undas et al. (2001) reported studies in healthy, male, nonsmoking medical students aged 21 to 24 years using a controlled method for producing microvascular injury. They found that the Pl(A2) variant was associated with enhanced thrombin generation and impaired antithrombotic action of aspirin at the site of microvascular injury. Neonatal Alloimmune Thrombocytopenia and Posttransfusion Purpura Pl(A) is the alloantigen most frequently implicated in syndromes of immune-mediated platelet destruction, particularly neonatal alloimmune thrombocytopenia and posttransfusion purpura (Newman et al., 1989). Hip Fracture, Susceptibility to Tofteng et al. (2007) analyzed the L33P polymorphism in 9,233 randomly selected Danish individuals, of whom 267 had a hip fracture (see 166710) during a 25-year follow-up period. Individuals homozygous for L33P had a 2-fold greater risk of hip fracture compared to noncarriers (p = 0.02), with risk confined primarily to postmenopausal women, in whom the hazard ratio was 2.6 after adjustment for age at menopause and use of hormone replacement therapy. (less)
|
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risk factor
(Jan 01, 2007)
|
no assertion criteria provided
Method: literature only
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MYOCARDIAL INFARCTION, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034773.7
First in ClinVar: Apr 04, 2013 Last updated: Jul 09, 2022 |
Comment on evidence:
The molecular basis of the platelet-specific alloantigen system Pl(A) is a 1565T-C transition in exon 2 of the ITGB3 gene, resulting in a leu33-to-pro (L33P) … (more)
The molecular basis of the platelet-specific alloantigen system Pl(A) is a 1565T-C transition in exon 2 of the ITGB3 gene, resulting in a leu33-to-pro (L33P) substitution which corresponds to Pl(A1) and Pl(A2), respectively (Newman et al., 1989). Pl(A) is also known as alloantigen Zw. Kim et al. (1995) determined the allelic frequencies of Pl(A1) and Pl(A2) in African Americans, whites, and Koreans living in the metropolitan Baltimore area. Myocardial Infarction, Susceptibility to Using a monoclonal antibody that specifically distinguished Pl(A1) from Pl(A2), Weiss et al. (1995) observed an unexpected high frequency of family members homozygous for the A2 allele in kindreds with a high prevalence of acute coronary events at a relatively young age (under 60 years). In a case-control study, Weiss et al. (1996) found that the A2 allele was 2.1 times more prevalent among 71 patients with myocardial infarction (see 608446) or unstable angina than among controls (39.4% vs 19.1%, respectively; P = 0.01). In a subgroup of patients whose disease began before the age of 60 years, the prevalence of the A2 allele was 50%, a value that was 3.6 times that among control subjects under 60 years of age (13.9%; P = 0.002), yielding an odds ratio (OR) of 2.8 for those with the A2 allele. In patients less than 60 years of age at the onset of disease, the OR was 6.2. Goldschmidt-Clermont et al. (1996) reported without supporting data that the other major polymorphisms were not associated with myocardial infarction: Ko(a), Ko(b), Bak(a), Bak(b), Pen(a), Pen(b), Br(a), and Br(b). Goldschmidt-Clermont et al. (1996) presented evidence that Sergei Grinkov, twice Olympic pairs figure skating gold medalist, was heterozygous for the A1/A2 polymorphism and suggested that this may have been related to his precocious coronary artery disease. Grinkov, aged 28, collapsed suddenly while training on the ice rink in Lake Placid, New York, and could not be resuscitated. Necropsy showed severe coronary artery disease and a recent (4- to 6-hour-old) anteroseptal myocardial infarction (MI). He had never sought medical attention for a heart problem. He was not a smoker, did not use drugs or medications, did not have hypertension or diabetes mellitus, his total cholesterol and lipid profiles were unremarkable, and he trained for several hours daily. Significantly, his father died suddenly at the age of 52 years. See the lay account by Grinkov's widow, Ekaterina Gordeeva (1996). Goldschmidt-Clermont et al. (1999) genotyped 116 asymptomatic sibs (60 Caucasians, 56 Afro-Caribbeans) of patients with coronary heart disease manifested before the age of 60 years for the Pl(A) polymorphism. A control cohort consisted of 268 individuals (168 Caucasians, 100 Afro-Caribbeans) who were matched for race and geographic area but were free of coronary heart disease. The authors also characterized the sib cohort for other atherogenic and thrombogenic risk factors. The results supported the hypothesis that the prevalence of Pl(A2)-positive individuals is high in kindreds with premature coronary heart disease. Hence, like the established risk factors that tend to cluster in families with premature coronary heart disease and contribute strongly to the accelerated atherosclerotic process affecting these individuals, the Pl(A2) polymorphism of GP IIIa may represent an inherited risk that promotes the thromboembolic complications of coronary heart disease. That these asymptomatic sibs had overall less-established risk factors than their Pl(A1) counterparts may provide an explanation for why they remained asymptomatic despite their Pl(A2) positivity. In a cross-sectional study of patients with a history of myocardial infarction and in matched controls from the Finnish population, Pastinen et al. (1998) analyzed common variants of 8 genes implicated previously as risk factors for coronary heart disease or MI. The most common low density lipoprotein receptor (LDLR; 606945) mutations in Finland were also included in the analysis. Multiplex genotyping of the target genes was performed using a specific and efficient array-based minisequencing system. The 4G allele of the PAI1 (173360) gene (P less than 0.05) and the Pl(A2) allele of the glycoprotein IIIa gene (P less than 0.01) were associated with an increased risk of MI in the Finnish study population. They found that the combined effect of these risk alleles conferred a high risk for the development of MI (OR = 4.5, P = 0.001), which was particularly prominent in male subjects (OR = 6.4, P = 0.0005). The observation of 2 separate genes contributing an additive risk of developing MI exemplified the advantages of multiplex analysis of genetic variation. Undas et al. (2001) reported studies in healthy, male, nonsmoking medical students aged 21 to 24 years using a controlled method for producing microvascular injury. They found that the Pl(A2) variant was associated with enhanced thrombin generation and impaired antithrombotic action of aspirin at the site of microvascular injury. Neonatal Alloimmune Thrombocytopenia and Posttransfusion Purpura Pl(A) is the alloantigen most frequently implicated in syndromes of immune-mediated platelet destruction, particularly neonatal alloimmune thrombocytopenia and posttransfusion purpura (Newman et al., 1989). Hip Fracture, Susceptibility to Tofteng et al. (2007) analyzed the L33P polymorphism in 9,233 randomly selected Danish individuals, of whom 267 had a hip fracture (see 166710) during a 25-year follow-up period. Individuals homozygous for L33P had a 2-fold greater risk of hip fracture compared to noncarriers (p = 0.02), with risk confined primarily to postmenopausal women, in whom the hazard ratio was 2.6 after adjustment for age at menopause and use of hormone replacement therapy. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort. | Nurden AT | Human mutation | 2015 | PMID: 25728920 |
Integrin beta3 Leu33Pro polymorphism and risk of hip fracture: 25 years follow-up of 9233 adults from the general population. | Tofteng CL | Pharmacogenetics and genomics | 2007 | PMID: 17264806 |
Pl(A2) polymorphism of beta(3) integrins is associated with enhanced thrombin generation and impaired antithrombotic action of aspirin at the site of microvascular injury. | Undas A | Circulation | 2001 | PMID: 11723016 |
The Pl(A2) polymorphism of integrin beta(3) enhances outside-in signaling and adhesive functions. | Vijayan KV | The Journal of clinical investigation | 2000 | PMID: 10727448 |
Higher prevalence of GPIIIa PlA2 polymorphism in siblings of patients with premature coronary heart disease. | Goldschmidt-Clermont PJ | Archives of pathology & laboratory medicine | 1999 | PMID: 10583927 |
Array-based multiplex analysis of candidate genes reveals two independent and additive genetic risk factors for myocardial infarction in the Finnish population. | Pastinen T | Human molecular genetics | 1998 | PMID: 9700201 |
Clues to the death of an Olympic champion. | Goldschmidt-Clermont PJ | Lancet (London, England) | 1996 | PMID: 8667943 |
A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. | Weiss EJ | The New England journal of medicine | 1996 | PMID: 8598867 |
A monoclonal antibody (SZ21) specific for platelet GPIIIa distinguishes P1A1 from P1A2. | Weiss EJ | Tissue antigens | 1995 | PMID: 8838346 |
Gene frequencies of the five major human platelet antigens in African American, white, and Korean populations. | Kim HO | Transfusion | 1995 | PMID: 7570918 |
The molecular genetic basis of Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in Israel. | Newman PJ | Proceedings of the National Academy of Sciences of the United States of America | 1991 | PMID: 2014236 |
Gordeeva, E. My Sergei--A Love Story. New York: Warner Books, Inc. 1996. | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/55e31015-4a08-43d4-8768-dba28433a961 | - | - | - | - |
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Text-mined citations for rs5918 ...
HelpRecord last updated Mar 23, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.